The present invention relates to hydroxamic acid derivatives, the methods for preparation thereof and inhibitors of interleukin-6 production comprising thereof, as an active ingredient.
More particularly, it relates to (1) inhibitors of IL-6 production comprising hydroxamic acid derivatives of the formula (I) 
(wherein all the symbols have the same meaning as defined hereinafter), non-toxic salts thereof and prodrugs thereof, as an active ingredient,
(2) novel hydroxamic acid derivatives of the above formula (I), non-toxic salts thereof and prodrugs thereof and
(3) the methods for preparation of hydroxamic acid derivatives of the above formula (I), non-toxic salts thereof and prodrugs thereof.
Cytokine is a multifunctional factor which plays an important role in the host defense system of living body and it relates to various life phenomena. However, there are many diseases which may be caused by overproduction thereof or overresponse thereto.
IL-6 is a cytokine produced from various cells, e.g. T cells, B cells, macrophages, kidney mesangial cells, fibroblasts, and its various physiological effects are known e.g. induction of B cells differentiation to antibody-producing cells, activation of T cells, increase of platelets, and production of acute phase protein from liver cells. But an abnormal production of IL-6 has been observed in various inflammations, autoimmune diseases and neoplastic diseases and it is suggested that IL-6 plays a certain role in the causes of such pathophysiological situations. In the experiment using an animal model in which IL-6 was forcibly expressed, various types of diseases could be observed and such results strongly suggest the existence of relationship between the abnormal production of IL-6 and the cause of certain diseases (Biochem. J., 265, 621 (1990), Immunol. Today, 11, 443 (1990), J. Autoimmun., 5 Suppl A, 123 (1992), Clin. Immunol. Immunopathol., 62, S60 (1992)).
Therefore inhibition of IL-6 production is expected to improve various kinds of diseases such as inflammatory diseases as a representative. The present invention is targeted for the cytokine and provides novel medicines through inhibiting the production thereof.
Clinical application of the compounds of the present invention involves those diseases which may be caused and be changed to worse by abnormal production of IL-6 or by overresponse to them. Inhibitors of IL-6 production may be used for the prevention and/or treatment of various inflammatory diseases, sepsis, multiple myeloma, plasma cell leukemia, osteoporosis, cachexia, psoriasis, nephritis, renal cell carcinoma, Kaposi""s sarcoma, rheumatoid arthritis, hypergammaglobulinemia, Castleman""s disease, atrial myxoma, diabetes mellitus, autoimmne diseases, hepatitis, colitis, graft versus host disease, infectious diseases and endometriosis (J. Immunol., 145, 4185 (1990), J. Exp. Med., 172, 1505 (1990), J. Clin. Invest., 87, 739 (1991), J. Clin. Invest., 89, 1681 (1992), EMBO J., 13, 1189 (1994), Hematol. Oncol. Clin. North Am., 11, 159 (1997), Cytokines Cell Mol. Ther., 4(3), 161 (1998), Folia Med. (Plovdiv), 41(1), 78 (1999), JPEN J. Parenter Enteral Nutr., 23(5), S20 (1999), J. Infect. Dis., 180(1), 10 (1999), Am. J. Obstet. Gynecol., 176(3), 593 (1997)).
For example, in the specification of Japanese Patent Application Kokai S59-46244, it is described that hydroxamic acid derivatives of the formula (X)
AXxe2x80x94BXxe2x80x94(CH2)nXxe2x80x94CONHOHxe2x80x83xe2x80x83(X)
[wherein AX is RXXXmX (RX is phenyl, pyrrolyl, thienyl, imidazolyl or thiazolyl, XX is halogen, lower alkyl, lower alkoxy or nitro, mX is 0 or an integer of 1-2 and each XX is the same or different optionally.), BX is xe2x80x94CHOHxe2x80x94, xe2x80x94CHxe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94CO, nX is an integer of 2-10.]
is useful as anti-parasite agent.
And in the U.S. Pat. No. 4,769,461, it is described that hydroxamic acid derivatives of the formula (Y) 
[wherein WY is a bond, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR2Yxe2x80x94, xe2x80x94CH(OH)xe2x80x94or xe2x80x94NR2Y xe2x80x94COxe2x80x94, XY is N or CR2Y,
when nY=0, YY is O, S, NR2Y or C(R2Y)2 
when nY=1, YY is N or CR2Y,
ZY is xe2x80x94CH2Oxe2x80x94, xe2x80x94CH2Sxe2x80x94, xe2x80x94CH2NR2yxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR2xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94CONR2Yxe2x80x94, xe2x80x94CHR2YCHR2Yxe2x80x94, xe2x80x94C(R2Y)xe2x95x90C(R2Y)xe2x80x94 or xe2x80x94Cxe2x89xa1Cxe2x80x94,
R1Y is hydrogen, lower alkyl, trifluoromethyl, nitro, hydroxy, lower alkoxy, mercapto, lower alkylthio or halogen,
R2Y is hydrogen or lower alkyl,
nY is 0 or 1,
mY is 1-6.
With the proviso that when WY is a bond, then mY is 0-5.]
is useful as antiinflammatory or anti-allergy agent by inhibition of cyclooxygenase and lipoxygenase.
Energetic investigations have been carried out to discover a compound possessing an inhibitory activity of IL-6 production. As a results, the present inventors have found that the purpose has been achieved by hydroxamic acid derivatives of the formula (I) or non-toxic salts thereof.
Hydroxamic acid derivatives of the formula (I) of the present invention have not been known as inhibitors of IL-6 production at all. Further, almost hydroxamic acid derivatives of the formula (I), non-toxic salts thereof and prodrugs thereof are novel compounds which are not known at all.
The present invention relates to
1) an inhibitor of IL-6 production comprising hydroxamic acid derivatives of the formula (I), 
[wherein, R1 is
(a) C1-8 alkyl,
(b) C2-8 alkenyl,
(c) C2-8 alkynyl,
(d) halogen,
(e) nitro,
(f) nitrile,
(g) trifluoromethyl,
(h) trifluoromethoxy,
(i) xe2x80x94OR2,
(j) xe2x80x94SR2,
(k) xe2x80x94NR3R4,
(l) xe2x80x94COR5,
(m) keto,
(n) Cyc1,
(o) C1-8 alkyl substituted by xe2x80x94OR2, xe2x80x94SR2, xe2x80x94NR3R4, xe2x80x94COR5 or Cyc1,
(p) xe2x80x94SO2R10,
(q) (C1-8 alkylene)xe2x80x94OR11,
(r) C1-8 alkyl substituted by nitrile, xe2x80x94SO2R10 or xe2x80x94Oxe2x80x94(C1-8 alkylene)xe2x80x94OR11,
(s) xe2x80x94Oxe2x80x94(C1-8 alkylene)xe2x80x94NR12R13,
(t) xe2x80x94Sxe2x80x94(C1-8 alkylene)xe2x80x94NR12R13,
(u) C1-8 alkyl substituted by xe2x80x94Oxe2x80x94(C1-8 alkylene)xe2x80x94NR12R13xe2x80x94 or xe2x80x94Sxe2x80x94(C1-8 alkylene)xe2x80x94NR12R13,
(v) C2-8 alkenyl substituted by xe2x80x94OR2, xe2x80x94SR2, xe2x80x94NR3R4, xe2x80x94COR5, Cyc1, nitrile, xe2x80x94SO2R10, xe2x80x94Oxe2x80x94(C1-8 alkylene)xe2x80x94OR11, xe2x80x94Oxe2x80x94(C1-8 alkylene)xe2x80x94NR12R13 or xe2x80x94Sxe2x80x94(C1-8 alkylene)xe2x80x94NR12R13 or
(w) C2-8 alkynyl substituted by xe2x80x94OR2, xe2x80x94SR2, xe2x80x94NR3R4, xe2x80x94COR5, Cyc1, nitrile, xe2x80x94SO2R10, xe2x80x94Oxe2x80x94(C1-8 alkylene)xe2x80x94OR11, xe2x80x94Oxe2x80x94(C1-8 alkylene)xe2x80x94NR12R13 or xe2x80x94Sxe2x80x94(C1-8 alkylene)xe2x80x94NR12R13,
R2 is hydrogen, C1-8alkyl, C2-9 acyl or Cyc1,
R3 and R4 are each independently hydrogen, C1-8 alkyl, C2-9 acyl or Cyc1,
R5 is hydroxy, C1-8 alkyl, C1-8 alkoxy, xe2x80x94NR6R7 or Cyc1,
R6 and R7 are each independently hydrogen, C1-8 alkyl or Cyc1,
R10 is C1-8 alkyl or Cyc1,
Cyc1 is C3-7 monocarbocyclic ring or 5-7 membered mono-cyclic hetero ring containing 1-4 nitrogen atom(s), one oxygen atom and/or one sulfur atom,
R11 is hydrogen, C1-8 alkyl, C2-9 acyl or Cyc1,
R12 and R13 are each independently hydrogen, C1-8 alkyl, C2-9 acyl or Cyc1,
m is 0 or an integer of 1-5,
ring A is C3-15 mono-, bi- or tri-carbocyclic ring or 5-18 membered mono-, bi- or tri-cyclic hetero ring containing 1-4 nitrogen atom(s), 1-2 oxygen atom(s) and/or 1-2 sulfur atom(s),
ring B is C5-15 mono-, bi- or tri-carbocyclic aryl or 5-18 membered mono-, bi- or tricyclic hetero aryl containing 1-4 nitrogen atom(s), 1-2 oxygen atom(s) and/or 1-2 sulfur atom(s),
E is a bond, xe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94Cxe2x89xa1Cxe2x80x94,
R8 is
(a) C1-8 alkyl,
(b) C1-8 alkoxy,
(c) halogen,
(d) nitro,
(e) nitrile,
(f) trifluoromethyl or
(g) trifluoromethoxy.
With the proviso that when E is a bond, then R1 and R8, taken together, may be optionally C1-4 alkylene.
n is 0 or an integer of 1-5,
R9 is hydrogen, C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl.],
nontoxic salts thereof or prodrugs thereof, as an active ingredient,
2) Hydroxamic acid derivatives of the formula (I) 
[wherein, R1 is
(a) C1-8 alkyl,
(b) C2-8 alkenyl,
(c) C2-8 alkynyl,
(d) halogen,
(e) nitro,
(f) nitrile,
(g) trifluoromethyl,
(h) trifluoromethoxy,
(i) xe2x80x94OR2,
(j) xe2x80x94SR2,
(k) xe2x80x94NR3R4,
(l) xe2x80x94COR5,
(m) keto,
(n) Cyc1,
(o) C1-8 alkyl substituted by xe2x80x94OR2, xe2x80x94SR2, xe2x80x94NR3R4, xe2x80x94COR5 or Cyc1,
(p) xe2x80x94SO2R10,
(q) xe2x80x94Oxe2x80x94(C1-8 alkylene)xe2x80x94OR11,
(r) C1-8 alkyl substituted by nitrile, xe2x80x94SO2R10 or xe2x80x94Oxe2x80x94(C1-8 alkylene)xe2x80x94OR11,
(s) xe2x80x94Oxe2x80x94(C1-8 alkylene)xe2x80x94NR12R13,
(t) xe2x80x94Sxe2x80x94(C1-8 alkylene)xe2x80x94NR12R13,
(u) C1-8 alkyl substituted by xe2x80x94Oxe2x80x94(C1-8 alkylene)xe2x80x94NR12R13xe2x80x94 or xe2x80x94Sxe2x80x94(C1-8 alkylene)xe2x80x94NR12R13,
(v) C2-8 alkenyl substituted by xe2x80x94OR2, xe2x80x94SR2, xe2x80x94NR3R4, xe2x80x94COR5, Cyc1, nitrile, xe2x80x94SO2R10, xe2x80x94Oxe2x80x94(C1-8 alkylene)xe2x80x94OR11, xe2x80x94Oxe2x80x94(C1-8 alkylene)xe2x80x94NR12R13 or xe2x80x94Sxe2x80x94(C1-8 alkylene)xe2x80x94NR12R13 or
(w) C2-8 alkynyl substituted by xe2x80x94OR2, xe2x80x94SR2, xe2x80x94NR3R4, xe2x80x94COR5, Cyc1, nitrile, xe2x80x94SO2R10, xe2x80x94Oxe2x80x94(C1-8 alkylene)xe2x80x94OR11, xe2x80x94Oxe2x80x94(C1-8 alkylene)xe2x80x94NR12R13 or xe2x80x94Sxe2x80x94(C1-8 alkylene)xe2x80x94NR12R13 or
R2 is hydrogen, C1-8 alkyl, C2-9 acyl or Cyc1,
R3 and R4 are each independently hydrogen, C1-8 alkyl, C2-9 acyl or Cyc1,
R5 is hydroxyl, C1-8 alkyl, C1-8 alkoxy, xe2x80x94NR6R7 or Cyc1,
R6 and R7 are each independently hydrogen, C1-8 alkyl or Cyc1,
R10 is C1-8 alkyl or Cyc1,
Cyc1 is C3-7 mono-carbocyclic ring or 5-7 membered mono-cyclic hetero ring containing 1-4 nitrogen atom(s), one oxygen atom and/or one sulfur atom,
R11 is hydrogen, C1-8 alkyl, C2-9 acyl or Cyc1,
R12 and R13 are each independently hydrogen, C1-8 alkyl, C2-9 acyl or Cyc1,
m is 0 or an integer of 1-5,
ring A is C3-15 mono-, bi- or tri-carbocyclic ring or 5-18 membered mono-, bi- or tri-cyclic hetero ring containing 1-4 nitrogen atom(s), 1-2 oxygen atom(s) and/or 1-2 sulfur atom(s),
ring B is C5-15 mono-, bi- or tri-carbocyclic aryl or 5-18 membered mono-, bi- or tri-cyclic hetero aryl containing 1-4 nitrogen atom(s), 1-2 oxygen atom(s) and/or 1-2 sulfur atom(s),
E is a bond, xe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94Cxe2x89xa1Cxe2x80x94,
R8 is
(a) C1-8 alkyl,
(b) C1-8 alkoxy,
(c) halogen,
(d) nitro,
(e) nitrile,
(f) trifluoromethyl or
(g) trifluoromethoxy.
With the proviso that when E is a bond then R1 and R8, taken together, is C1-4 alkylene optionally.
n is 0 or an integer of 1-5,
R9 is hydrogen, C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl.
With the proviso that when E is xe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94Cxe2x89xa1Cxe2x80x94, ring A is C3-7 mono-carbocyclic ring or 5-7 membered mono-cyclic hetero ring containing 1-4 nitrogen atom(s), one oxygen atom and/or one sulfur atom.],
nontoxic salts thereof or prodrugs thereof,
3) the methods for preparation of hydroxamic acid derivatives of the above formula (I), non-toxic salts thereof and prodrugs thereof.
Unless otherwise specified, all isomers are included in the present invention. For example, alkyl, alkoxy and alkylene groups include straight or branched ones. In addition, isomers on double bond, ring, fused ring (E-, Z-, cis-, trans-isomer), isomers generated from asymmetric carbon atom(s) (R-, S-, xcex1-, xcex2-isomer, enantiomer, diastereomer), optically active isomer (D-, L-, d-, l-, (+)-, (xe2x88x92)-isomer), polar compounds generated by chromatographic separation (more polar compound, less polar compound), equilibrium compounds, mixtures thereof at voluntary ratios and racemic mixtures are also included in the present invention.
In the present invention, C1-8 alkyl means methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and the isomers thereof.
C2-8 alkenyl means vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, butadienyl, pentadienyl, hexadienyl, heptadienyl, octadienyl, hexatrienyl, heptatrienyl, octatrienyl and the isomer thereof.
C2-8 alkynyl means ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, butadiynyl, pentadiynyl, hexadiynyl, heptadiynyl, octadiynyl, hexatriynyl, heptatriynyl, octatriynyl and the isomer thereof.
Halogen means fluoride, chloride, bromide and iodide.
C1-4 alkylene means methylene, ethylene, trimethylene, tetramethylene and the isomers thereof.
C1-8 alkylene means methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene and isomers thereof.
C2-9 acyl means acetyl, propionyl, butyryl, valeryl, hexanoyl, heptanoyl, octanoyl, nonanoyl and the isomers thereof.
C1-8 alkoxy means methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy and the isomers thereof.
C3-7 mono-carbocyclic ring means C3-7 mono-aromatic carbocyclic ring, partially saturated carbocyclic ring thereof and fully saturated carbocyclic ring thereof. It includes, for example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclopentene, cyclohexene, cycloheptene, cyclopentadiene, cyclohexadiene, cycloheptadiene and benzene etc.
5-7 membered mono-cyclic hetero ring containing 1-4 nitrogen atom(s), one oxygen atom and/or one sulfur atom means 5-7 membered mono-cyclic hetero aryl containing 1-4 nitrogen atom(s), one oxygen atom and/or one sulfur atom and partially or fully saturated one. It includes, for example, pyrrole, imidazole, pyrazole, triazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepine, oxazepine, thiophene, thiain (thiopyran), thiepine, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, oxazine, oxadiazine, oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine, thiadiazepine, pyrroline, pyrrolidine, imidazoline, imidazolidine, pyrazoline, pyrazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, dihydropyridine, dihydropyrimidine, dihydropyridazine, piperidine, piperazine, tetrahydropyrimidine, tetrahydropyridazine, dihydroazepine, dihydrodiazepine, tetrahydroazepine, tetrahydrodiazepine, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrothiophene, tetrahydrothiophene, dihydrothiain (dihydrothiopyran), tetrahydrothiain (tetrahydrothiopyran), dihydrooxazole, tetrahydrooxazole, dihydroisoxazole, tetrahydroisoxazole, dihydrothiazole, tetrahydrothiazole, dihydroisothiazole, tetrahydroisothiazole, tetrahydroxadiazole, tetrahydroxazine, tetrahydroxadiazine, tetrahydroxazepine, tetrahydroxadiazepine, tetrahydrothiadiazole, tetrahydrothiazine, tetrahydrothiadiazine, tetrahydrothiazepine, tetrahydrothiadiazepine, morpholine and thiomorpholine etc.
C3-15 mono-, bi- or tri-carbocyclic ring means C3-15 mono-, bi- and tri-aromatic carbocyclic ring, partially saturated carbocyclic ring thereof and fully saturated carbocyclic ring thereof. It includes, for example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclopentene, cyclohexene, cycloheptene, cyclopentadiene, cyclohexadiene, cycloheptadiene, benzene, pentalene, indene, naphthalene, azulene, fluorene, phenanthrene, anthracene, acenaphthylene, biphenylene, perhydropentalene, perhydroindene, dihydronaphthalene, tetrahydronaphthalene, perhydronaphthalene, perhydroazulene, perhydrofluorene, perhydrophenanthrene, perhydroanthracene, perhydroacenaphthylene and perhydrobiphenylene, etc.
5-18 membered mono-, bi- or tri-cyclic hetero ring containing 1-4 nitrogen atom(s), 1-2 oxygen atom(s) and/or 1-2 sulfur atom(s) means 5-18 membered mono-, bi- or tri-cyclic hetero aryl containing 1-4 nitrogen atom(s), 1-2 oxygen atom(s) and/or 1-2 sulfur atom(s) and partially or fully saturated one. It includes, for example, pyrrole, imidazole, pyrazole, triazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepine, oxazepine, thiophene, thiain (thiopyran), thiepine, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, oxazine, oxadiazine, oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine, thiadiazepine, indole, isoindole, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, indazole, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole, benzothiazole, benzimidazole, carbazole, acridine, dibenzofuran, dibenzothiophene, pyrroline, pyrrolidine, imidazoline, imidazolidine, pyrazoline, pyrazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, dihydropyridine, dihydropyrimidine, dihydropyridazine, piperidine, piperazine, tetrahydropyrimidine, tetrahydropyridazine, dihydroazepine, dihydrodiazepine, tetrahydroazepine, tetrahydrodiazepine, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrothiophene, tetrahydrothiophene, dihydrothiain (dihydrothiopyran), tetrahydrothiain (tetrahydrothiopyran), dihydrooxazole, tetrahydrooxazole, dihydroisoxazole, tetrahydroisoxazole, dihydrothiazole, tetrahydrothiazole, dihydroisothiazole, tetrahydroisothiazole, tetrahydrooxadiazole, tetrahydrooxazine, tetrahydrooxadiazine, tetrahydrooxazepine, tetrahydrooxadiazepine, tetrahydrothiadiazole, tetrahydrothiazine, tetrahydrothiadiazine, tetrahydrothiazepine, tetrahydrothiadiazepine, morpholine, thiomorpholine, indoline, isoindoline, dihydrobenzofuran, perhydrobenzofuran, dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene, perhydrobenzothiophene, dihydroisobenzothiophene, perhydroisobenzothiophene, dihydroindazole, dihydroquinoline, tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine, dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline, dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline, dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole, dihydrobenzimidazole, perhydrobenzimidazole, benzoxazepine, benzoxadiazepine, benzothiazepine, benzothiadiazepine, benzazepine, benzodiazepine, indroxoazepine, indrotetrahydroxazepine, indroxadiazepine, indrotetrahydroxadiazepine, indrothiazepine, indrotetrahydrothiazepine, indrothiadiazepine, indrotetrahydrothiadiazepine, indroazepine, indrotetrahydroazepine, indrodiazepine, indrotetrahydrodiazepine, benzofurazan, benzothiadiazole, benzotriazole, imidazothiazole, dihydrocarbazole, tetrahydrocarbazole, perhydrocarbazole, dihydroacridine, tetrahydroacridine, perhydroacridine, dihydrodibenzofuran, dihydrodibenzothiophene, tetrahydrodibenzofuran, tetrahydrodibenzothiophene, perhydrodibenzofuran, perhydrodibenzothiophene, 1,3-dioxaindan and 1,4-dioxotetrahydronaphthalene.
C5-15 mono-, bi- or tri-carbocyclic aryl means cyclopentadiene, cyclohexadiene, cycloheptadiene, cycloheptatriene, benzene, indene, naphthalene, fluorene and anthracene etc.
5-18 membered mono-, bi- or tri-cyclic hetero aryl containing 1-4 nitrogen atom(s), 1-2 oxygen atom(s) and/or 1-2 sulfur atom(s) means pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepine, thiophene, thiain (thiopyran), thiepine, oxazole, isoxazole, thiazole, isothiazole, furazan, oxadiazole, oxazine, oxadiazine, oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine, thiadiazepine, indole, isoindole, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, indazole, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole, benzothiazole, benzimidazole, benzoxepine, benzoxazepine, benzoxadiazepine, benzothiepine, benzothiazepine, benzothiadiazepine, benzazepine, benzodiazepine, benzofurazan, benzothiadiazole, benzotriazole, carbazole, acridine, dibenzofuran and dibenzothiophene.
In the present invention, unless otherwise specified, as will be apparent to those skilled in the art, a symbol  represents bonding to back of the paper (that is, xcex1-configuration),  represents bonding to front of the paper (that is, xcex2-configuration),  represents xcex1-, xcex2- or mixture thereof and  represents mixture of xcex1-configuration and xcex2-configuration.
[Salts]
Non-toxic salts of the present invention include all non-toxic salts, for example, general salts, acid addition salts, hydrate salts.
The compounds of the present invention may be converted into the corresponding salts by conventional means. Water-soluble salts are preferred. Suitable salts, for example, include:
salts of alkali metals (e.g. potassium, sodium), salts of alkaline earth metals (e.g. calcium, magnesium), ammonium salts, salts of pharmaceutically acceptable organic amines (e.g. tetramethylammonium, triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris(hydroxymethyl)amine, lysine, arginine, N-methyl-D-glucamine).
The compounds of the present invention may be converted into the corresponding acid addition salts by conventional means. Water-soluble salts are preferred. Suitable salts, for example, include:
salts of inorganic acids e.g. hydrochloride, hydrobromide, sulfate, phosphate, nitrate; salts of organic acids e.g. acetate, trifluoroacetate, lactate, tartrate, oxalate, fumarate, maleate, citrate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, isethionate, glucuronate, gluconate.
The compounds of the present invention and salts thereof may be converted into the corresponding hydrates by conventional means.
Furthermore, the prodrugs of the present invention means the compounds that xe2x80x94CONHOH group of the formula (I) is converted to 
(wherein, R14 is C1-8 alkyl substituted by C1-8 alkyl or C1-8 alkoxy) or 
Among the compounds of the present invention, preferred ring A is C3-10 mono-, bi-carbocyclic ring or 5-10 membered mono-, bi-cyclic hetero ring containing 1-4 nitrogen atom(s), 1-2 oxygen atom(s) and/or 1-2 sulfur atom(s). Especially, C5-7 mono-carbocyclic ring or 5-10 membered mono-, bi-cyclic hetero ring containing 1-4 nitrogen atom(s), 1-2 oxygen atom(s) and/or 1-2 sulfur atom(s) is preferable. Benzene, cyclohexane, benzoxazole, benzothiazole, benzimidazole, benzothiophene or benzofuran is more preferable.
Preferred R1 is (1) C1-8 alkyl, (2) xe2x80x94OR2, (3) xe2x80x94SR2, (4) halogen, (5) Cyc1, (6) xe2x80x94NR3R4 or (7) C1-8 alkyl substituted by xe2x80x94OR2, xe2x80x94SR2, halogen, Cyc1, xe2x80x94NR3R4. Especially, (1) C1-8 alkyl, (2) C1-8 alkoxy, (3) C1-8 alkylthio, (4) halogen, (5) 5-7 membered mono-cyclic hetero ring containing 1-4 nitrogen atom(s), one oxygen atom and/or one sulfur atom, (6) di(C1-8 alkyl)amino or (7) C1-8 alkyl substituted by C1-8 alkoxy, C1-8 alkylthio, halogen, 5-7 membered mono-cyclic hetero ring, di(C1-8 alkyl)amino is preferable. Methyl, methoxy, methylthio, chloride, dimethylamino, dipropylamino, morpholine, piperidine, piperazine, methoxymethyl, methylthiomethyl, dimethylaminomethyl, dipropylaminomethyl, morpholine-1-ylmethyl, piperidine-1-ylmethyl or piperazine-1-ylmethyl is more preferable.
Preferred stereoisomer of hydroxy group is R configuration, S configuration or mixture thereof. Especially, R or S configuration is preferable. S configuration is more preferable.
Preferred E is, preferably, a bond, xe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94Cxe2x89xa1Cxe2x80x94 and a bond or xe2x80x94Cxe2x89xa1Cxe2x80x94 is preferable.
Preferred B ring is C1-5 mono- or bi-carbocyclic aryl or 5-15 membered mono- or bi-cyclic hetero aryl. Especially, benzene, naphthalene, pyridine, thiophene, benzofuran or benzoxazole is preferable.
Preferred R8 is C1-4 alkyl. Especially, methyl is preferable.
Preferred R9 is hydrogen, C1-4 alkyl, C2-4 alkenyl or C2-4 alkynyl. Especially, hydrogen, methyl or allyl is preferable.
Preferred m is 0 or an integer of 1-5. Especially, 0 or 1 is preferable.
Preferred n is 0 or an integer of 1-5. Especially, 0 or 1 is preferable.
In the present invention, preferred compounds are compounds prepared in example hereinafter, shown in the following table 1 to 7 and salts thereof etc.
[Methods for Preparation of the Compounds of the Present Invention]
Hydroxamic acid derivatives of the formula (I) in the present invention, non-toxic salts thereof and prodrugs thereof may be prepared by the following methods or the methods described in examples.
[1] Among the compounds of the present invention, the prodrugs of the formula (IA) may be prepared by the following methods of (a)-(c).
(a) Among the prodrugs of the formula (IA), the compounds in which R1 doesn""t represent a group containing amino, thiol and carboxy, that is, the compounds of the formula (IA-a) 
(wherein, R1-a has the same meaning as R1. With the proviso that R1-a doesn""t represent a group containing of amino, thiol and carboxy and the other symbols have the same meaning as defined hereinbefore.) may be prepared by amidation of the compounds of the formula (II) 
(wherein, all the symbols have the same meaning as defined hereinbefore.) and the compounds of the formula (III)
H2Nxe2x80x94OR14xe2x80x83xe2x80x83(III)
(wherein, R14 has the same meaning as defined hereinbefore.).
The amidation is known. For example, it may be carried out
(1) by the method with using acid halide,
(2) by the method with using mixed acid anhydride,
(3) by the method with using conducing agent etc.
Concrete description of these methods are as follows:
(1) The method with acid halide may be carried out, for example; carboxylic acid is reacted with an acid halide (oxalyl chloride or thionyl chloride etc.) in an organic solvent (chloroform, methylene chloride, diethyl ether or tetrahydrofuran etc.) or without solvents at from xe2x88x9220xc2x0 C. to a refluxing temperature to give an acid halide. The obtained acid halide and an amine are reacted in an organic solvent (chloroform, methylene chloride, diethyl ether or tetrahydrofuran etc.) in the presence of tertiary amine (pyridine, triethylamine, dimethylaniline or dimethylaminopyridine etc.), at 0-40xc2x0 C. Also this reaction may be carried out by the reaction with amine and acid halide in an organic solvent (dioxane or tetrahydrofuran etc.), with an aqueous alkali solution (solution of bicarbonate or solution of sodium hydroxide etc.) at 0-40xc2x0 C.
(2) The method with mixed acid anhydride may be carried out, for example; carboxylic acid is reacted with an acid halide (pivaloyl chloride etc.) or an acid derivative (ethyl chloroformate or isobutyl chloroformate etc.) in an organic solvent (chloroform, methylene chloride, diethyl ether or tetrahydrofuran etc.) or without solvents, in the presence of tertiary amine (pyridine, triethylamine, dimethylaniline or dimethylaminopylidine etc.), at 0-40xc2x0 C. The mixed acid anhydride is reacted with an amine in an organic solvent (chloroform, methylene chloride, diethyl ether or tetrahydrofuran etc.) at 0-40xc2x0 C.
(3) The method with condensing agent may be carried out, for example; a carboxylic acid and an amine are reacted in an organic solvent (chloroform, methylene chloride, dimethylformamide, diethyl ether or tetrahydrofuran etc.) or without solvents in the presence or absence of tertiary amine (pyridine, triethylamine, dimethylaniline or dimethylaminopyridine etc.) using with condensing agent (1,3-dicyclohexylcarbodiimido (DCC), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimido (EDC), 1,1xe2x80x2-carbonyidiimidazole (CDI), 2-chloro-1-methylpyridinium iodide or 1-propanephosphonic acid cyclic anhydride (PPA) etc.) using or without 1-hydroxybenzotriazole (HOBt) at 0-40xc2x0 C.
Preferably, the above reactions (1), (2) and (3) are carried out under an atmosphere of an inert gas (argon, nitrogen etc.) on anhydrous condition.
(b) Among the prodrugs of the formula (IA), the above compounds of the formula (IA-a) may be prepared by coupling reaction with the compounds of the formula (IV) 
(wherein, X is halogen and the other symbols have the same meaning as defined hereinbefore.) and the compounds of the formula (V) 
(wherein all the symbols have the same meaning as defined hereinbefore.) or the compounds of the formula (VI) 
(wherein all the symbols have the same meaning as defined hereinbefore.).
The reaction is known. For example, it may be carried out in an organic solvent (benzene, dimethylformamide, dioxane, tetrahydrofuran, methanol, acetonitrile, dimethoxyethane or acetone etc.) in the presence of a base (sodium ethylate, sodium hydroxide, potassium hydroxide, triethylamine, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, cesium carbonate, thallium carbonate, tripotassium phosphate, cesium fluoride, barium hydroxide or tetrabutylammonium fluoride etc.) and a catalyst (tetrakis(triphenylphosphine)palladium (Pd(PPh3)4), dichlorobis(triphenylphosphine)palladium (PdCl2(PPh3)2), palladium acetate (Pd(OAc)2), palladium black, 1,1-bis(diphenylphosphinoferrocene)dichloro palladium (PdCl2(dppf)2), dichlorodiallylpalladium (PdCl2(allyl)2) or iodephenylbis(triphenylphosphine)palladium (PhPdl(PPh3)2) etc.) at room temperature xe2x88x92120xc2x0 C.
(c) Among the prodrugs of the formula (IA), the compounds in which R1 is a group containing at least one of amino, thiol or carboxy, i.e., the compounds of the formula (IA-c) 
(wherein, R1-c is a group containing at least one of amino, thiol or carboxy and the other symbols have the same meaning as defined hereinbefore.) may be prepared by the removal of a protecting group in the compounds of the formula (IA-a) in which amino, thiol or carboxy is protected by a protecting group, i.e., the compounds (IA-a1) 
(wherein, R1-a1 is a group containing at least one of protected amino, protected thiol or protected carboxy and the other symbols have the same meaning as defined hereinbefore.).
A protecting group of amino includes, for example, benzyloxycarbonyl, allyloxycarbonyl, t-butoxycarbonyl, trifluoroacetyl or 9-fluorenylmethoxycarbonyl.
A protecting group of thiol includes, for example, benzyl, methoxybenzyl, acetoamidemethyl, triphenylmethyl or acetyl.
A protecting group of carboxy includes, for example, methyl, ethyl, t-butyl, benzyl or allyl.
The protecting group of amino, thiol or carboxy includes the above one, in addition, the other protecting group which is removable selectively and easily, for example, one described in T. W. Greene et. al., Protective Groups in Organic Synthesis, Third Edition, Wiley-Interscience, New York, 1999.
The removal of a protecting group of amino, thiol or carboxy is well known. For example, it is
(1) the removal of a protecting group in an alkaline condition,
(2) the removal of a protecting group in an acidic condition,
(3) the removal of a protecting group by hydrogenelysis, or
(4) the removal of a protecting group using metal complex etc.
Concrete description of these methods are as follows:
(1) The removal of protecting group in an alkaline condition may be carried out, for example, in an organic solvent (methanol, tetrahydrofuran or dioxane etc.) with hydroxide of alkaline metal (sodium hydroxide, potassium hydroxide or lithium hydroxide etc.), hydroxide of alkaline earth metal (barium hydroxide or calcium hydroxide etc.), carbonate (sodium carbonate or potassium carbonate etc.), or an aqueous solution thereof or a mixture thereof at 0-40xc2x0 C.
(2) The removal of protecting group in an acidic condition may be carried out, for example, in an organic solvent (dichloromethane, chloroform, dioxane, ethyl acetate or anisole etc.), organic acid (acetic acid, trifluoroacetic acid or methanesulfonic acid) or inorganic acid (hydrochloric acid or sulfuric acid etc.), or a mixture thereof (hydrogen bromide/acetic acid etc.) at 0-100xc2x0 C.
(3) The removal of a protecting group by hydrogenelysis may be carried out, for example, in a solvent (ether (tetrahydrofuran, dioxane, dimethoxyethane or diethylether etc.), alcohol(methanol or ethanol etc.), benzene(benzene or toluene etc.), ketone (acetone or methylethylketone etc.), nitrile (acetonitrile etc.), amido (dimethylformamide etc.), water, ethyl acetate, acetic acid or a mixture thereof etc.) in the presence of a catalyst (palladium-carbon, palladium black, palladium hydroxide, platinum oxide, raney nickel etc.), at atmospheric or reduced pressure under an atmosphere of hydrogen or ammonium formate at 0-200xc2x0 C.
(4) The removal of a protecting group using metal complex may be carried out, for example, in an organic solvent (dichloromethane, dimethylformamide or tetrahydrofuran etc.) in the presence of a trap reagent (tributyltin hydride or dimedone etc.) and/or an organic acid (acetic acid etc.) with metal complex (tetrakis(triphenylphosphine)palladium(0) complex etc.) at 0-40xc2x0 C.
As well known to the person in the art, the aimed compounds of present invention may be prepared easily by choice of these reaction.
[2] Among the compounds of the present invention, hydroxamic acid derivatives of the formula (I) may be prepared by the method of (d) or (e).
(d) Among hydroxamic acid derivatives of the formula (I), the compound wherein R1 doesn""t represent a group containing amino, thiol or carboxy, i.e., the compound of the formula (I-d) 
(wherein, all the symbols have the same meaning as defined hereinbefore.) may be prepared by the amidation with the compound of the above formula (II) and hydroxyamine (H2Nxe2x80x94OH).
The amidation may be carried out by the same procedure as described hereinbefore.
(e) Hydroxamic acid derivatives of the formula (I) may be prepared by the removal of a protecting group of the compounds of the above formula (IA).
The removal of a protecting group of the hydroxamic acid is known. For example, it is
(1) the removal of a protecting group in an alkaline condition,
(2) the removal of a protecting group in an acidic condition, or
(3) the removal of a protecting group by hydrogenelysis etc.
The removal of a protecting group may be carried out by the same procedure as described hereinbefore.
The reaction of the removal of a protecting group of hydroxamic acid in the present invention means an ordinal one which is well known to the person in the art, for example, the removal of a protecting group in an alkaline condition, the removal of a protecting group in an acidic condition or the removal of a protecting group by hydrogenelysis. The aimed compounds of the present invention may be prepared easily by choice of these reaction.
As well known to the person in the art, a protecting group of hydroxamic acid includes, for example, t-butyl, xe2x80x94C(CH3)2xe2x80x94OCH3 and benzyl. In addition, such a group includes the other protecting group which is removable selectively and easily, for example, one described in T. W. Greene et. al., Protective Groups in Organic Synthesis, Third Edition, Wiley-Interscience, New York, 1999.
[3] Among the compounds of the present invention, the prodrugs of the formula (IB) may be prepared by the removal of the methanol in the compounds of the formula (IA) wherein R14 is 1-methoxy-1-methylethyl, i.e., the compounds of the formula (IA-3) 
(wherein, all the symbols have the same meaning as defined hereinbefore.).
The reaction of the removal of methanol is known. For example, it may be carried out in an organic solvent (benzene, toluene, dioxane or pyridine etc.) at 60-1 50xc2x0 C.
The compounds of the formula (II) and (IV) are known per se or may be prepared according to the following Reaction Scheme 1 and Reaction Scheme 2 or by known methods easily. 
In reaction scheme,
R101 is C1-4 alkyl or xe2x80x94CH2CH2OCH2CH2OCH3,
R1-a, R8, R9, R14, ring A, ring B, E, m, n or X have the same meaning as defined hereinbefore.
In above reaction schemes, each reaction may be carried out by each conventional technique. Further, in above reaction scheme, the compounds of the formula (X), (XIV), (III), (V) and (VI) used as starting materials have been known per se or may be prepared by known methods easily.
In each reaction in the present specification, obtained products may be purified by conventional techniques. For example, purification may be carried out by distillation at atmospheric or reduced pressure, by high performance liquid chromatography, by thin layer chromatography or by column chromatography using silica gel or magnesium silicate, by washing or by recrystallization. Purification may be carried out after each reaction, or after a series of reactions.
The other starting materials and each test compounds in the present invention have been known per se or may be prepared by known methods.
[Pharmacological Activities of the Compounds of the Present Invention]
According to following experiments, it is confirmed that the compound of the present invention has an inhibitory activity on IL-6 production.
[Method]
1.5xc3x97104 of A549 cells (human lung epithelial cell line) were suspended in 100 xcexcL of Dulbecco""s Modified Eagle Medium (DMEM) containing 0.5% fetal bovine serum (abbreviated as FBS) and incubated for a day and night in 96 well-microplate. 20 xcexcL of the test compound dissolved in dimethylsulfoxide (DMSO) at various concentrations and 80 xcexcL of tumor necrosis factor-xcex1 (TNF-xcex1 (Genzyme Co., cat. No. TNF-H)) dissolved in serum-free DMEM at the concentration of 12.5 ng/mL were added thereto. After the incubation for 24 hours, the supernatant (100 xcexcL) was collected to measure the amount of IL-6 being produced using enzyme linked immuno solvent assay (ELISA) (RandD Systems Co., cat. No. D6050). Then the inhibitory activity of the test compound was calculated and the 50% inhibitory concentration (IC50) was determined. For example, the IC50 value of the compound of example 3 was 0.052 xcexcM.
[Method]
3.0xc3x97103 of synovial cells from rheumatoid arthritis patients were suspended in 200 xcexcL of DMEM containing 10% FBS and incubated for a day and night in 96 well-microplate, followed by the incubation for 5 hours in serum-free DMEM. 20 xcexcL of the test compound dissolved in DMSO at various concentrations and 80 xcexcL of interleukin-1xcex2 (IL-1xcex2 (Genzyme Co., cat. No. 80-3688-01)) dissolved in DMEM containing 2.5% fetal bovine serum at the concentration of 5 ng/mL were added thereto. After the incubation for 24 hours, the supernatant (100 xcexcL) was collected to measure the amount of IL-6 being produced using ELISA (RandD Systems Co., cat. No. D6050). Then the inhibitory activity of the test compound was calculated and the 50% inhibitory concentration (IC50) was determined. For example, the IC50 value of the compound of example 3 was 0.041 xcexcM.
[Method]
Eight weeks old female DA rats were used. During the experimental period, they were housed in animal room artificially kept the room temperature of 24xc2x12xc2x0 C., humidity of 55xc2x15%, and 12 hours interval of light and dark cycle. They had free access to a standard solid pellet chow (CE-2, Japan CLEA) and drinking tap water, and were used for the experiment after a week acclimation. The collagen-induced arthritis was performed by the following method. After the mixing of bovine type II collagen (0.3% collagen solution, KOKEN #K41, lot. 11214, abbreviated as CII), incomplete Freund""s adjuvant (DIFCO #0639-60) and saline with the ratio of 1:2:1, the mixture was then ultra-sonicated to form emulsion for 20 secondsxc3x973 times at 1 minute interval. The intradermal injection of 0.1 mL of the emulsion (0.75 mg of CII/mL) was performed on each four different portions of the back on day 0. A week after the first immunization, arthritis was elicited by the intradermal injection of 0.15 mL of the emulsion at the basal portion of the tail. The test compound was suspended in 0.5% carboxymethylcellulose solution, and was administered orally in the morning and evening twice a day from day 0 to day 28. According to the method of Osterman T. et al. (Inflamm. Res., 44, 258-263, 1995), the severity of arthritis was judged and scored. The hind paw volume of each animal was also measured with the plethysmometer (UNICOM, TK-101CMP). For example, 10 mg/kg/day (b.i.d.) of the compound of the example 3 completely inhibited the development of arthritis, and the example 3 even at the dose of 3 mg/kg/day showed significant inhibition by approximately 60% on the arthritis score and the hind paw edema.
[Toxicity]
The toxicity of the compounds of formula (I) of the present invention, nonoxic salts thereof or prodrugs thereof is very low and therefore the compounds may be considered safe for pharmaceutical use.
[Application for Pharmaceuticals]
The compounds of the present invention possess an inhibitory activity of IL-6 production in animal, especially human, so they are useful for the prevention and/or treatment of, for example, various inflammatory diseases, sepsis, multiple myeloma, plasma cell leukemia, osteoporosis, cachexia, psoriasis, nephritis, renal cell carcinoma, Kaposi""s sarcoma, rheumatoid arthritis, hypergammaglobulinemia , Castleman""s disease, atrial myxoma, diabetes mellitus, autoimmne diseases, hepatitis, colitis, graft versus host disease, infectious diseases and endometriosis.
For the purpose above described, the compounds of formula (I), non-toxic salts thereof or prodrugs thereof may be normally administered systemically or locally, usually by oral or parenteral administration.
The doses to be administered are determined depending upon, for example, age, body weight, symptom, the desired therapeutic effect, the route of administration, and the duration of the treatment. In the human adult, the doses per person are generally from 1 mg to 1000 mg, by oral administration, up to several times per day, and from 0.1 mg to 100 mg, by parenteral administration (preferably intravenous administration), up to several times per day, or continuous administration from 1 to 24 hours per day from vein.
As mentioned above, the doses to be used depend upon various conditions. Therefore, there are cases in which doses lower than or greater than the ranges specified above may be used.
The compounds of the present invention may be administered in the form of, for example, solid forms for oral administration, liquid forms for oral administration, injections, liniments or suppositories for parenteral administration.
Solid forms for oral administration include compressed tablets, pills, capsules, dispersible powders, and granules. Capsules include hard capsules and soft capsules.
In such solid forms, one or more of the active compound(s) may be admixed with vehicles (such as lactose, mannitol, glucose, microcrystalline cellulose, starch), binders (such as hydroxypropyl cellulose, polyvinylpyrrolidone or magnesium metasilicate aluminate), disintegrants (such as cellulose calcium glycolate), lubricants (such as magnesium stearate), stabilizing agents, and solution adjuvants (such as glutamic acid or aspartic acid) and prepared according to methods well known in normal pharmaceutical practice. The solid forms may, if desired, be coated with coating agents (such as sugar, gelatin, hydroxypropyl cellulose or hydroxypropylmethyl cellulose phthalate), or be coated with two or more films. And further, coating may include containment within capsules of absorbable materials such as gelatin.
Liquid forms for oral administration include pharmaceutically acceptable solutions, suspensions and emulsions, syrups and elixirs. In such forms, one or more of the active compound(s) may be dissolved, suspended or emulized into diluent(s) commonly used in the art (such as purified water, ethanol or a mixture thereof). Furthermore, such liquid forms may also comprise some additives, such as wetting agents, suspending agents, emulsifying agents, sweetening agents, flavoring agents, aroma, preservative or buffering agent.
Injections for parenteral administration include sterile aqueous, suspensions, emulsions and solid forms which are dissolved or suspended into solvent(s) for injection immediately before use. In injections, one or more of the active compound(s) may be dissolved, suspended or emulized into solvent(s). The solvents may include distilled water for injection, physiological salt solution, vegetable oil, propylene glycol, polyethylene glycol, alcohol, e.g. ethanol, or a mixture thereof. Injections may comprise some additives, such as stabilizing agents, solution adjuvants (such as glutamic acid, aspartic acid or POLYSORBATE80 (registered trade mark)), suspending agents, emulsifying agents, soothing agent, buffering agents, preservative. They may be sterilized at a final step, or may be prepared and compensated according to sterile methods. They may also be manufactured in the form of sterile solid forms such as freeze-dried products, which may be dissolved in sterile water or some other a sterile diluent(s) for injection immediately before use.
Other forms for parenteral administration include liquids for external use, IL-6 ointments and endermic liniments, inhalations, sprays, suppositories and pessaries for vaginal administration which comprise one or more of the active compound(s) and may be prepared by methods known per se.
Sprays may comprise additional substances other than diluents, such as stabilizing agents (such as sodium sulfate), isotonic buffers (such as sodium chloride, sodium citrate or citric acid). For preparation of such sprays, for example, the method described in the U.S. Pat. No. 2,868,691 or U.S. Pat. No. 3,095,355 may be used.